An Expeditious Route toward Pyrazine-Containing Nucleoside

Jan 7, 2011 - M. Bhanuchandra , Alexandre Baralle , Shinya Otsuka , Keisuke Nogi ... Akio Kamimura , Masahiro So , Shingo Ishikawa , and Hidemitsu Uno...
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An Expeditious Route toward Pyrazine-Containing Nucleoside Analogues Sachin G. Modha,† Jalpa C. Trivedi,†,‡ Vaibhav P. Mehta,†,§ Denis S. Ermolat’ev,† and Erik V. Van der Eycken*,† † Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, B-3001, Leuven, Belgium. ‡Present address: Department of Chemistry, Shoolini University, Bhajol, Solan-173 229, Himachal Pradesh, India. § Present address: Institut fur Organische and Biomoleculare Chemie, Georg-August-Universit€ at G€ ottingen, Tamannstr. 2, Goettingen 37077, Germany

[email protected] Received October 21, 2010

An improved and convenient methodology for the synthesis of asymmetrically substituted pyrazines starting from 3,5-dichloropyrazin-2(1H)-ones has been elaborated. Several nucleoside analogues have been synthesized containing the pyrazine core as the organic base coupled with the sugar via a triazole linkage. The beneficial effect of microwave irradiation throughout the sequence has been demonstrated.

Introduction Nucleosides possess a broad spectrum of biological functions, ranging from their primary role as building blocks in the genetic code to other functions, such as biosynthetic intermediates, energy donors, metabolic regulators, and cofactors in enzymatic processes. Many nucleoside analogues have been developed for screening as antiviral agents, nonradioactive fluorescent labels for DNA, and as anticancer drugs, by variation of the sugar part and/or the heterocyclic base.1 As a result, nucleosides and their analogues have generated considerable scientific interest in their chemistry and biology.2 A substantial number of naturally occurring

and synthetic nucleosides, many with interesting biological activities, have been prepared via a variety of approaches.3 Although pyrimidine-like nucleosides have been studied extensively, pyrazine-based nucleosides were still missing from this array until recently.4 Therefore, we reasoned that it might be worthwhile to investigate the use of substituted pyrazines as alternative organic bases of the nucleoside. Tri- and tetrasubstituted pyrazines are present in the core structure of a number of important natural as well as synthetic heterocyclic compounds, such as, for example, flavor components in food.5 Especially, pyrazines substituted with a thioether function are known to possess a nice aroma.

(1) (a) De Clercq, E.; Holy, A.; Rosenberg, I.; Sakuma, T.; Balzarini, J.; Maudgal, P. C. Nature 1986, 323, 464. (b) Haines, D. R.; Tseng, C. K.; Marquez, V. E. J. Med. Chem. 1987, 30, 943. (c) Borcherding, D. R.; Narayanan, S.; Hasobe, M.; McKee, J. G.; Keller, B. T.; Borchardt, R. T. J. Med. Chem. 1988, 31, 1729. (d) Naesens, L.; Snoeck, R.; Andrei, G.; Balzarini, J.; Neyts, J.; De Clercq, E. Antiviral Chem. Chemother. 1997, 8, 1. (e) Agrofoglio, L. A.; Challand, S. R. Acyclic, Carbocyclic and L-Nucleosides; Kluwer Academic: Dordrecht, The Netherlands, 1998; pp 174-284. (f) Kim, H. S.; Barak, D.; Harden, K. T.; Boyer, J. L.; Jacobson, K. A. J. Med. Chem. 2001, 44, 3092. (2) (a) Suhadolnik, R. J., Ed. Nucleosides as Biological Probes; John Wiley & Sons: New York, 1979. (b) Townsend, L. B., Ed. Chemistry of Nucleosides and Nucleotides; Plenum Press: New York, 1988; Vol. 1; 1991; Vol. 2. (c) Chu, C. K., Baker, D. C., Eds. Nucleosides and Nucleotides as Antitumor and Antiviral Agents; Plenum Press: New York, 1993. (d) Townsend, L. B., Ed. Chemistry of Nucleosides and Nucleotides; Plenum Press: New York, 1994; Vol. 3.

(3) (a) Ermolat’ev, D. S.; Mehta, V. P.; Van der Eycken, E. V. QSAR Comb. Sci. 2007, 26, 1266. (b) Robins, M. J.; Yang, H.; Miranda, K.; Peterson, M. A.; De Clercq, E.; Balzarini, J. J. Med. Chem. 2009, 52, 3018. (c) De Clercq, E. Nucleosides, Nucleotides Nucleic Acids 2009, 28, 586. (d) Romeo, G.; Chiacchio, U.; Corsaro, A.; Merino, P. Chem. Rev. 2010, 110, 3337. (e) Lakshman, M. K.; Singh, M. K.; Parrish, D.; Balachandran, R.; Day, B. W. J. Org. Chem. 2010, 75, 2461. (4) (a) Benner, S. A. U.S. patent US006140496A, 2000, p 24. (b) Liu, W.; Wise, D. S.; Townsend, L. B. J. Org. Chem. 2001, 66, 4783. (c) Von Krosigk, U.; Benner, S. A. Helv. Chim. Acta 2004, 87, 1299. (5) (a) Koehler, P. E.; Odell, G. V. J. Agric. Food Chem. 1970, 18, 895. (b) Maga, J. A.; Sizer, C. E. J. Agric. Food Chem. 1973, 21, 22. (c) Mega, J. A. In Pyrazines in Food: An Update; Furia, T. E., Ed.; Critical Reviews in Food Sciences and Nutrition; CRC: Boca Raton, FL, 1982; Vol. 16, pp 1-48. (d) Leunissen, M.; Davidson, V. J.; Kakuda, Y. J. Agric. Food Chem. 1996, 44, 2694. (e) Wailzer, B.; Klocker, J.; Buchbauer, G.; Ecker, G.; Wolschann, P. J. Med. Chem. 2001, 44, 2805.

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DOI: 10.1021/jo102089h r 2011 American Chemical Society

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FIGURE 1. Examples of pharmacologically active molecules having a pyrazine core.

Moreover, they are versatile synthetic intermediates.6 Many substituted pyrazines possess important pharmacological activities, such as antiviral7 (Figure 1, compounds I and II), ATR kinase inhibitor8 (Figure 1, compound III), antimutagenic,9 vascular endothelial growth factor inhibitory activity,10 or as epithelial sodium channel blockers.11 Despite their importance, only a limited number of synthetic methodologies are described for the generation of asymmetrically multisubstituted pyrazines.12 We have previously explored the application of 3,5-dichloropyrazin-2(1H)-ones as attractive starting materials for the synthesis of different heterocyclic compounds.13 We envisaged that the pyrazinone framework offers a unique gateway for the generation of asymmetrically tri- and tetrasubstituted pyrazines (Scheme 1). The substituent in the C6-position of the pyrazinone is determined by the aldehyde used during its construction,14 whereas the substituent at the C3-position could be easily introduced via reaction of the imidoyl chloride moiety.15 The pyrazinone can be converted to the pyrazine-thione by Lawesson’s reagent, followed by (6) Barlin, G. B. The Chemistry of Heterocyclic Compounds; Wiley: New York, 1982; Vol. 41. (7) (a) Walker, J. A.; Liu, W.; Wise, D. S.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 1998, 41, 1236. (b) De Clercq, E. Med. Res. Rev. 2010, 30, 667. (8) Jean-Damien, C.; et al. et al. PCT Int. Appl. 2010, WO2010054398A1. (9) (a) Pettit, G. R.; Inoue, M.; Kamano, Y.; Herald, D. L.; Arm, C.; Dufresne, C.; Christie, N. D.; Schmidt, J. M.; Doubek, D. L.; Krupa, T. S. J. Am. Chem. Soc. 1996, 118, 10672. (b) Pettit, G. R.; Inoue, M.; Kamano, Y.; Herald, D. L.; Arm, C.; Dufresne, C.; Christie, N. D.; Schmidt, J. M.; Doubek, D. L.; Timothy, S. K. J. Am. Chem. Soc. 1998, 110, 2006. (c) Garg, N. K.; Stolz, B. M. Tetrahedron Lett. 2005, 46, 2423. (d) Neelamkavil, S.; Arison, B.; Birzin, E.; Feng, J.-J.; Chen, K.-H.; Lin, A.; Cheng, F. C.; Taylor, L.; Thornton, E. R.; Smith, A. B.; Hirschmann, R. J. Med. Chem. 2005, 48, 4025. (10) Kuo, G. H.; DeAngelis, A.; Emanuel, S.; Wang, A.; Zhang, Y.; Connolly, P. J.; Chen, X.; Gruninger, R. H.; Rugg, C.; Pesquera, A. F.; Middleton, S. A.; Jolliffe, L.; Murray, W. V. J. Med. Chem. 2005, 48, 4535. (11) Hirsh, A. J.; Molino, B. F.; Zhang, J.; Astakhova, N.; Geiss, W. B.; Sargent, B. J.; Swenson, B. D.; Usyatinsky, A.; Wyle, M. J.; Boucher, R. C.; Smith, R. T.; Zamurs, A.; Johnson, M. R. J. Med. Chem. 2006, 49, 4098. (12) (a) Ohta, A.; Itoh, R.; Kaneko, Y.; Koike, H.; Yuasa, K. Heterocycles 1989, 29, 939. (b) Buchi, G.; Galindo, J. J. Org. Chem. 1991, 56, 2605. (c) Heathcock, C. H.; Smith, S. C. J. Org. Chem. 1994, 59, 6828. (d) Drogemuller, M.; Flessner, T.; Jautelat, R.; Scholz, U.; Winterfeldt, E. Eur. J. Org. Chem. 1998, 2811. (e) McCullough, K. J. In Rodd’s Chemistry of Carbon Compounds, 2nd ed.; Sainsbury, M., Ed.; Elsevier: Amsterdam, 2000; Vol. 4 (Parts I and J), p 99. (f) Elmaaty, T. A.; Castle, L. W. Org. Lett. 2005, 7, 5529. (g) Aparicio, D.; Attanasi, O. A.; Filippone, P.; Ignacio, R.; Lillini, S.; Mantellini, F.; Palacios, F.; de los Santos, J. M. J. Org. Chem. 2006, 71, 5897. (h) Taber, D. F.; DeMatteo, P. W.; Taluskie, K. V. J. Org. Chem. 2007, 72, 1492. (i) Candelon, N.; Shinkaruk, S.; Bennetau, B.; Bennetau-Pelissero, C.; Dumartin, M.-L.; Degueil, M.; Babin, P. Tetrahedron 2010, 66, 2463. (13) Van der Eycken, E., Kappe, C. O., Eds. Topics in Heterocyclic Chemistry; Springer: Berlin, Germany, 2006; Vol. 1, p 267. (14) Vekemans, J.; Pollers-Wieers, C.; Hoornaert, G. J. Heterocycl. Chem. 1983, 20, 919. (15) Kaval, N.; Bisztray, K.; Dehaen, W.; Kappe, C. O.; Van der Eycken, E. Mol. Diversity 2003, 7, 125. (16) Mehta, V. P.; Sharma, A.; Van Hecke, K.; Van Meervelt, L.; Van der Eycken, E. J. Org. Chem. 2008, 73, 2382.

removal of the p-methoxybenzyl group and simultaneous conversion of the thione to the methyl thioether.16 In the newly generated pyrazines, the chlorine becomes susceptible toward the Sonogashira cross-coupling reaction with trimethylsilylacetylene. After desilylation, affording the corresponding ethynyl pyrazine,17,3a a Huisgen [3 þ 2] cycloaddition could be performed on this terminal acetylene with a suitable sugar azide.18 Finally, the methyl thioether group is involved in a Liebeskind-Srogl19 cross-coupling reaction, giving the asymmetrically substituted pyrazine coupled with a sugar moiety via a triazole linkage. Results and Discussion Pyrazin-2(1H)-ones 1a-c were alkoxylated at the C3position using NaH, giving quantitative yields of 2a-c (Scheme 2). Treatment of 1d with Me4Sn under Stille conditions provided methylated compound 2d in 95% yield. All C3-substituted pyrazine-2(1H)-ones 2a-d were reacted with Lawesson’s reagent in toluene at reflux temperature to afford the corresponding thioamides 3a-d in good yields (Scheme 2). A mixture of compound 3a with 5 equiv of methyl iodide and 10 mol % of iodine in toluene was refluxed for 12 h, yielding 72% of the expected methylthioether 4a together with 20% of p-methoxybenzylthioether 5a as the main byproduct (Table 1, entry 1).16 The formation of 5a might be explained by the competitive reaction of the in situ formed p-methoxybenzyliodide. During the scale-up of the reaction, we noticed that it was rather difficult to separate the desired methylthioether 4a from the compound 5a due to similar polarity. Therefore, efforts were made to make this reaction more selective. However, under microwave irradiation, at a temperature of 130 °C for 30 min applying further the same conditions, the amount of byproduct 5a increased (Table 1, entry 2). The reaction was rather slow in the absence of iodine, still giving both 4a and 5a, with decreased yield (17) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467. (b) For a recent review, see: Agrofoligo, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev. 2003, 103, 1875. (c) Negishi, E. I.; Anastasia, L. Chem. Rev. 2003, 103, 1979. (d) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874. (e) Douchet, H.; Hierso, J. C. Angew. Chem., Int. Ed. 2007, 46, 834. (f) Plenio, H. Angew. Chem., Int. Ed. 2008, 47, 6954. (18) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 40, 2004. (b) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057. (c) Kappe, C. O.; Van der Eycken, E. Chem. Soc. Rev. 2010, 39, 1280. (d) Appukkuttan, P.; Mehta, V. P.; Van der Eycken, E. V. Chem. Soc. Rev. 2010, 39, 1467 and references cited therein. (19) (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260. (b) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001, 3, 91. (c) Lengar, A.; Kappe, C. O. Org. Lett. 2004, 6, 771. (d) Singh, B. K.; Mehta, V. P.; Parmar, V. S.; Van der Eycken, E. Org. Biomol. Chem. 2007, 5, 2962. (e) Prokopcova, H.; Kappe, C. O. J. Org. Chem. 2007, 72, 4440. (f) Prokopcova, H.; Kappe, C. O. Angew. Chem., Int. Ed. 2009, 48, 2276 and references cited therein.

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SCHEME 1. Retrosynthetic Analysis for the Generation of Asymmetrically Substituted Pyrazines Coupled with a Sugar Moiety via a Triazole Linkage

SCHEME 2.

Synthesis of Pyrazin-2(1H)-thiones 3a-d

(Table 1, entry 3). This observation was rather interesting as only salt formation was expected with methyliodide. Clearly, upon heating,20 the intermediate salt loses p-methoxybenzyl iodide, forming 4a, and the in situ formed p-methoxybenzyliodide reacts with an other molecule of starting material 3a to give 5a. As it was impossible to minimize the competition between methyl iodide and in situ formed p-methoxybenzyl iodide, it was decided to exclude methyl iodide from the reaction mixture. This should result in the sole formation of p-methoxybenzylthioether 5a. As a proof of concept, when 3a was refluxed in toluene with 10 mol % of I2, to our satisfaction, only 5a was formed in 45% yield (Table 1, entry 4). Interestingly, when the solvent was changed to dichloromethane, the yield increased to 65% (Table 1, entry 5). When the reaction was run at rt with (20) Molina, P.; Alajarin, M.; Fresneda, P. M.; Lidon, M. J.; Vilaplana, M. J. Synthesis 1982, 7, 598.

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5, 10, 50, and 80 mol % of I2, respectively, there was not much change in yields, but a dramatic difference in reaction time was observed ranging from 40 to 0.15 h (Table 1, entries 8, 7, 9, and 10). The best condition was obtained when the reaction was carried out with 10 mol % of I2 in dichloromethane under microwave irradiation at 80 °C and a maximum power of 150 W for 15 min, yielding compound 5a in 83% yield (Table 1, entry 6). A plausible mechanism for the transfer of the p-methoxybenzyl group is shown in Scheme 3. Iodine first reacts with the sulfur atom of thioamide 3a to give intermediate A. This loses the p-methoxybenzyl group to form the unstable intermediates B and C that directly react with each other to give the p-methoxybenzylthioethers 5, while iodine goes back in the catalytic cycle. It is interesting to note that the reaction, which is rather slow at room temperature, is speeded up under microwave irradiation. To the best of our knowledge, there is no literature precedent about the transfer of a

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Modha et al. TABLE 1.

Optimization Study for Thioether Formationa

entry

reagent (equiv)

catalyst (mol %)

solvent

temp

time (h)

yield (%) 4a:5a

1b 2c 3 4 5 6d 7 8 9 10

MeI (5) MeI (5) MeI (5)

I2 (10) I2 (10)

toluene toluene toluene toluene DCM DCM DCM DCM DCM DCM

reflux 130 °C reflux reflux reflux 80 °C rt rt rt rt

12 0.5 1 12 6 0.25 24 40 6 0.15

72:20 55:30 40:15 0:45 0:65 0:83 0:79 0:73 0:80 0:85

I2 (10) I2 (10) I2 (10) I2 (10) I2 (5) I2 (50) I2 (80)

a

All the reactions were run on a 0.1 mmol scale of 3a with conventional heating unless otherwise stated. bScale-up reaction with 5 mmol of 3a was also done with full conversion, but it was not possible to separate 4a from 5a by column chromatography. cThe reaction mixture was irradiated using a maximum power of 400 W in a multimode microwave apparatus. dThe reaction mixture was irradiated using a maximum power of 150 W in a multimode microwave apparatus.

SCHEME 3. Plausible Mechanism for the Transfer of the p-Methoxybenzyl Group

p-methoxybenzyl group from nitrogen to sulfur in a p-methoxybenzyl-protected thioamide. This optimized protocol was applied to convert the pyrazin-2(1H)-thiones 3b-d into the corresponding p-methoxybenzylthioethers 5b-d, which were obtained in good yields (Scheme 4). In the newly generated pyrazines 5, the chlorine atom that was present at the C5-position of the starting pyrazinone is now susceptible for transition-metal-catalyzed cross-coupling reactions. However, to our surprise, all efforts made to perform a Sonogashira reaction met with failure (Table 2). This is in sharp contrast with our previously published work,16 where the reaction went smoothly when an S-Me group was present instead of an S-PMB group at the C2position of the pyrazine. Probably, the p-methoxybenzylthioether renders the chlorine less susceptible toward nucleophilic substitution by the palladium.

SCHEME 4. tives 5b-d

Synthesis of p-Methoxybenzylthioether Deriva-

Therefore, it seems obvious to substitute first the S-PMB group and then to check the reactivity of chlorine again. It was also interesting to know whether the S-PMB group should be reactive enough under standard Liebiskind-Srogl conditions. When pyrazine 5a was reacted with boronic acid 8a in the presence of copper(I)-thiophene-2-carboxylate and Pd(PPh3)4 in THF under conventional heating as well as under microwave irradiation (Table 3, entries 1-3, 5, and 6), poor to average yields were obtained. As the reaction was rather sluggish, it was assumed that reagents were getting decomposed during the long reaction time at high temperature. To overcome this difficulty, the reagents were added in two portions, and to our satisfaction, the reaction was complete in 1 h under microwave irradiation at 120 °C, yielding 9a in 84% (Table 3, entry 4).21 This optimized protocol was then applied for the conversion of 5a-d to 9b-j in good to excellent yields (Table 4). Having successfully established the optimized conditions for the pyrazine scaffold, we next explored the scope of the protocol for some other heterocycles bearing an S-PMB group. All starting compounds with a p-methoxybenzylthio or benzylthio group were synthesized according to literature procedures22 from their respective thiol derivative. (21) Singh, B. K.; Parmar, V. S.; Van der Eycken, E. Synlett 2008, 19, 3021. (22) Radi, M.; et al. ChemMedChem 2008, 3, 573.

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JOC Article TABLE 2.

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Attempts for the Sonogashira Cross-Coupling Reaction on Pyrazine 5aa

entry

R

Pd catalyst

Cu source

1 2 3 4 5 6

Me Me iso-propyl iso-propyl Me Me

Pd(PPh3)2Cl2 Pd(PPh3)2Cl2 Pd(PPh3)2Cl2 Pd(PPh3)2Cl2 Pd(OAc)2 Pd(OAc)2

CuI CuI CuI CuI CuI CuI

additive (equiv)

yield of 7 (%) b

TBAIc (1.2)

b b

TBAIc (1.2)

b

TBAIc (1.2)

b

b

a

Reactions were run on a 0.1 mmol scale of 5a, applying silyl acetylene (1.5 equiv), Pd catalyst (5 mol %), and a Cu source (10 mol %) using a mixture of DMF and triethylamine (1:1, 3 mL). The reactions were irradiated for 15 min at a 95 °C ceiling temperature using a maximum power of 75 W in a multimode microwave apparatus. bThe starting material was recovered. cTBAI = tetrabutylammoniumiodide.

TABLE 3.

Optimization Study for the Liebeskind-Srogl Cross-Coupling Reaction on the S-PMB Groupa

entry

boronic acid (equiv)

CuTC equiv

Pd(PPh3)4 mol %

temp °C (MWb/ΔT)

time (h)

ratioc (9a:5a)

1 2 3 4d 5 6d

3 5 1.1 2þ1 3 2þ1

3 5 1.2 1.5 þ 1 3 1.5 þ 1

5 10 3 5þ5 5 5þ5

100 (MW) 120 (MW) 100 (MW) 120 (MW) reflux (ΔT ) reflux (ΔT )

0.8 1.3 0.8 0.5 þ 0.5 10 4þ4

40:30 57:25 30:62 84:08 30:65 45:50

a All reactions were run on a 0.2 mmol scale of 5a in THF in sealed tubes. bA maximum power of 500 W in a multimode microwave apparatus was used. Ratio determined by GC-MS. dA fresh batch of reagents was added at the stipulated times. CuTC = copper(I)-thiophene-2-carboxylate.

c

Gratifyingly, applying our optimized protocol, the arylated products 11a-i were obtained in good to excellent yields (Scheme 5). However, the Liebeskind-Srogl crosscoupling reaction did not proceed in the case of isopropyl boronic acid. Similarly, no reaction occurred when 2-(4methoxybenxylthio)-1-methyl-1H-imidazole 10d was used (Scheme 5). As we were able to substitute the S-PMB group of compound 5 by an aryl group in compound 9, we reinvestigated the reactivity of the chlorine toward the Sonogashira reaction. To our delight, when a mixture of compound 9 with 1.5 equiv of triisopropylsilylacetylene, Pd(PPh3)2Cl2 (5 mol %), CuI (10 mol %), and TBAI (1.2 equiv) in DMF/TEA (1:1) was irradiated for 20 min at a ceiling temperature of 80 °C, a smooth reaction took place. Subsequent desilylation upon treatment of the crude compound with 1 M tetrabutylammonium fluoride (TBAF) in THF at rt yielded the desired terminal acetylenes 12a-d (Table 5), which were purified by simple filtration over silica gel. For the final step, all protected sugar azides23 and the benzyl azide24 13a-e (Figure 2) were synthesized according (23) (a) Stimac, A.; Kobe, J. Carbohydr. Res. 2000, 324, 149. (b) Stimac, A.; Kobe, J. Carbohydr. Res. 2000, 329, 317. (24) Ankati, H.; Biehl, E. Tetrahedron Lett. 2009, 50, 4677.

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to literature procedures. The coupling of the azides 13a-d with the generated pyrazines 12a-d was then investigated. A mixture of pyrazine 12 with 1.2 equiv of the protected sugar azide 13, 2 equiv of copper turnings, 5 mol % of CuSO4, and 5 mol % of tris-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine ligand (TBTA) in THF/i-PrOH/H2O (3:1:1, 5 mL) was irradiated at a 90 °C ceiling temperature using a maximum power of 200 W for 20 min. The Cu(I)-catalyzed [3 þ 2] dipolar cycloaddition reaction occurred with full regioselectivity, resulting in the formation of the corresponding 1,4-disubstituted 1,2,3-triazoles 14a-h in good yields (Table 6, entries 1-8). Reacting pyrazine 12d with benzyl azide, applying similar conditions, afforded 1,2,3triazole compound 14i in good yield (Table 6, entry 9). Interestingly, when pyrazine 12d was reacted with TMSazide, the corresponding desilylated 1,2,3-triazole product 14j was obtained. Conclusion In conclusion, we have developed a new and efficient synthetic procedure for the synthesis of differently substituted ethynyl pyrazines starting from 1-(4-methoxybenzyl)-3,5dichloropyrazin-2(1H)-ones. These newly generated ethynyl pyrazines can easily be coupled, via a triazole linkage, with

JOC Article

Modha et al. TABLE 4.

Liebeskind-Srogl Cross-Coupling Reaction on Pyrazines 5a

a Reactions were run on a 0.5 mmol scale of 5a-d, boronic acids (2 þ 1 equiv), Pd(PPh3)4 (5 þ 5 mol %), and CuTC (1.5 þ 1 equiv), in THF (4 mL). The mixture was irradiated in a sealed tube at a ceiling temperature of 120 °C and a maximum power of 500 W for 60 min in a multimode microwave apparatus. The reagents were added in two portions as stipulated; the second portion was added at half the reaction time (i.e., 30 min). CuTC = copper(I)-thiophene-2-carboxylate.

sugars applying a regioselective microwave-assisted Cu(I)catalyzed [3 þ 2] dipolar cycloaddition reaction, resulting in the formation of a small library of hitherto unknown nucleoside analogues. The application of microwave irradiation during different steps of the sequence has been shown to be highly valuable for speeding up reactions. We have also demonstrated that our newly optimized Liebeskind-Srogl protocol

is applicable for different heterocycles bearing a benzylthio ether functionality. Experimental Section General. Proton NMR spectra were recorded on a 300 MHz instrument using CDCl3 and DMSOd6 as solvents unless otherwise stated. The 1H and 13C chemical shifts are reported J. Org. Chem. Vol. 76, No. 3, 2011

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JOC Article SCHEME 5.

a

Modha et al.

Expanding the Scope of the Newly Developed Liebeskind-Srogl Cross-Coupling Procedure for Some Other Heterocyclesa

All the reactions were run on a 0.5 mmol scale of 10.

b

Only starting material was recovered.

in parts per million relative to tetramethylsilane as an internal standard. For the mass spectrometry, the ion source temperature was 150-250 °C, as required. High-resolution EI-mass spectra were performed with a resolution of 10 000. For chromatography, analytical TLC plates and 70-230 mesh silica gel were used. All the solvents and chemicals were purchased and used as available. Microwave Irradiation Experiments. All microwave irradiation experiments were carried out in a multimode Milestone MicroSYNTH microwave reactor (Laboratory Microwave Systems). This apparatus was used in the standard configuration as delivered, including proprietary software. Reactions were carried out in sealed microwave process vials (15, 50 mL), and the temperature control was performed using both external infrared and internal fiber optic sensors. The ramp time (time required to reach the expected temperature) was always between 1 and 2 min and is included in the total reaction time. The reaction mixture was continuously stirred during the reaction. After the irradiation, the reaction vessel was rapidly cooled by air jet cooling to the ambient temperature. General Procedure for the Preparation of 1a-d. The general procedure for the preparation of 1a-d is the same as previously described by our group.25 Data for compounds 1a,b,d are in accordance with the previously published work.25 1-(4-Methoxybenzyl)-3,5-dichloro-6-isobutylpyrazin-2(1H)one (1c): yellow solid; mp 118-120 °C; yield 44%; 1H NMR (300 MHz, CDCl3) δ 7.10 (d, J = 8.49 Hz, 2H), 6.86 (d, J = 8.67 Hz, 2H), 5.30 (s, 2H), 3.78 (s, 3H), 2.70 (d, J = 7.35 Hz, 2H),

2.14-2.03 (m, 1H), 1.05 (d, J = 6.57 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 159.4, 153.1, 143.8, 138.9, 128.3, 126.2, 124.7, 114.4, 55.3, 49.2, 37.8, 28.8, 22.4; HRMS (EI) calcd for C16H18Cl2N2O2 340.0745, found 340.0753. General Procedure for the Preparation of 2a-c. The general procedure for the preparation of 2a-c is the same as previously described by our group. Data for compounds 2a16 and 2b26 are in accordance with the previously published work. 1-(4-Methoxybenzyl)-5-chloro-3-ethoxy-6-isobutylpyrazin2(1H)-one (2c): white solid; mp 86-88 °C; yield 98%; 1H NMR (300 MHz, CDCl3) δ 7.09 (d, J = 8.67 Hz, 2H), 6.84 (d, J = 8.64 Hz, 2H), 5.25 (s, 2H), 4.39 (q, J = 7.14 Hz, 2H), 3.77 (s, 3H), 2.59 (d, J = 7.35 Hz, 2H), 1.99 (m, 1H), 1.46 (t, J = 6.96 Hz, 3H), 1.01 (d, J = 6.60 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 159.1, 152.9, 151.6, 129.5, 128.2, 127.4, 123.2, 114.2, 63.9, 55.2, 47.6, 37.3, 28.9, 22.3, 14.0; HRMS (EI) calcd for C18H23ClN2O3 350.1397, found 350.1389. General Procedure for the Preparation of 2d. The general procedure for the preparation of 2d is the same as previously described by our group.16 1-(4-Methoxybenzyl)-6-benzyl-5-chloro-3-methylpyrazin2(1H)-one (2d): white solid; mp 152-154 °C; yield 95%; 1H NMR (300 MHz, CDCl3) δ 7.38-7.29 (m, 3H), 7.11 (d, J = 6.78 Hz, 2H), 7.05 (d, J = 8.67 Hz, 2H), 6.87 (d, J = 8.85 Hz, 2H), 5.05 (s, 2H), 4.11 (s, 2H), 3.79 (s, 3H), 2.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.3, 156.4, 155.9, 134.7, 134.6, 129.3, 127.8, 127.5 (2), 127.0, 114.4, 55.3, 47.6, 35.2, 20.9; HRMS (EI) calcd for C20H19ClN2O2 354.1135, found 354.1134.

(25) Mehta, V. P.; Modha, S. G.; Ermolate’ev, D.; Van Hecke, K.; Van Meervelt, L.; Van der Eycken, E. V. Aust. J. Chem. 2009, 62, 27.

(26) Mehta, V. P.; Modha, S. G.; Van der Eycken, E. J. Org. Chem. 2008, 75, 976.

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Modha et al. TABLE 5.

Sonogashira Cross-Coupling Reaction of Pyrazines 9a,e,f,ha

a Reactions were run on a 2.0 mmol scale of 9a,e,f,h in a multimode microwave apparatus. bYields over two steps. TIPSA = triisopropylsilylacetylene, TBAI = tetrabutylammoniumiodide, and TBAF = tetrabutylammoniumfluoride.

General Procedure for the Preparation of 3a-d. The general procedure for the preparation of 3a-d is the same as previously described by our group.16 Data for compound 3a are in accordance with the previously published work.16 1-(4-Methoxybenzyl)-5-chloro-3-methoxy-6-methylpyrazine2(1H)-thione (3b): yellow solid; mp 127-129 °C; yield 88%; 1H NMR (300 MHz, CDCl3) δ 7.07 (d, J = 8.67 Hz, 2H), 6.84 (d, J = 8.76 Hz, 2H), 6.00 (s, 2H), 4.05 (s, 3H), 3.77 (s, 3H), 2.45 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.2, 159.2, 159.0, 131.0, 129.9, 127.6, 124.9, 114.4, 56.1, 55.3, 17.0; HRMS (EI) calcd for C14H15ClN2O2S 310.0543, found 310.0547. 1-(4-Methoxybenzyl)-5-chloro-3-ethoxy-6-isobutylpyrazine2(1H)-thione (3c): yellow liquid; 90% yield; 1H NMR (300 MHz, CDCl3) δ 6.99 (d, J = 8.49 Hz, 2H), 6.84 (d, J = 8.46 Hz, 2H), 5.99 (bs, 2H), 4.46 (q, J = 7.14 Hz, 2H), 3.77 (s, 3H), 2.71 (d, J = 7.14 Hz, 2H), 2.10-1.96 (m, 1H), 1.49 (t, J = 6.99 Hz, 3H), 1.01 (d, J = 6.60 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 159.1, 158.0, 133.5, 130.2, 130.0, 127.6, 127.2, 125.3, 114.3, 65.0, 55.2, 49.5, 38.1, 29.2, 24.6, 22.3, 15.6, 14.0; HRMS (EI) calcd for C18H23ClN2O2S 366.1169, found 366.1156. 1-(4-Methoxybenzyl)-6-benzyl-5-chloro-3-methylpyrazine2(1H)-thione (3d): yellow solid; mp 125-127 °C; yield 73%; 1H NMR (300 MHz, CDCl3) δ 7.37-7.34 (m, 3H), 7.08 (d, J = 6.6 Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 6.88 (d, J = 8.07 Hz, 2H), 5.81 (bs, 2H), 4.20 (s, 2H), 3.79 (s, 3H), 2.79 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 175.9, 163.8, 159.2, 138.4, 134.3, 134.1, 133.4, 132.3, 132.2, 132.1, 131.5 (2), 129.4, 128.5, 128.4, 127.7, 127.4, 127.2, 124.9, 114.5, 55.3, 36.0, 26.8; HRMS (EI) calcd for C20H19ClN2OS 370.0907, found 370.0912. General Procedure for the Preparation of 5a-d. Thioamide 3 (5 mmol) and iodine (10 mol %) were successively added to

JOC Article dichloromethane (15 mL) in a 50 mL glass vial. The resulting solution was irradiated at an 80 °C ceiling temperature for 15 min using a maximum microwave power of 150 W. After completion of the reaction, the reaction mixture was diluted with 200 mL of ethyl acetate and washed with sodium thiosulfate (5% in water, 100 mL) to remove iodine, followed by water (100 mL) and brine (100 mL). The organic layer was dried over magnesium sulfat and removed under reduced pressure, and the residue was purified by silica gel column chromatography (from 0 to 10% of ethyl acetate in heptane) to afford compounds 5a-d. 2-(4-Methoxybenzylthio)-5-chloro-3-methoxypyrazine (5a): light yellow solid; mp 79-81 °C; yield 83%; 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.31 (d, J = 8.46 Hz, 2H), 6.82 (d, J = 8.46 Hz, 2H), 4.32 (s, 2H), 4.00 (s, 3H), 3.78 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.8, 155.1, 144.2, 140.0, 133.8, 130.2, 128.9, 113.9, 55.2, 54.7, 32.8; HRMS (EI) calcd for C13H13ClN2O2S 296.0386, found 296.0394. 2-(4-Methoxybenzylthio)-5-chloro-3-methoxy-6-methyl-pyrazine (5b): off-white; mp 73-75 °C; yield 88%; 1H NMR (300 MHz, CDCl3) δ 7.33 (d, J = 8.67 Hz, 2H), 6.82 (d, J = 8.67 Hz, 2H), 4.32 (s, 2H), 3.96 (s, 3H), 3.78 (s, 3H), 2.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.7, 153.5, 142.6, 141.6, 138.4, 130.3, 129.3, 113.8, 55.2, 54.5, 32.8, 20.5; HRMS (EI) calcd for C14H15ClN2O2S 310.0543, found 310.0558. 2-(4-Methoxybenzylthio)-5-chloro-3-ethoxy-6-isobutyl-pyrazine (5c): colorless oil; yield 80%; 1H NMR (300 MHz, CDCl3) δ 7.32 (d, J = 8.46 Hz, 2H), 6.82 (d, J = 8.46 Hz, 2H), 4.38 (q, J = 6.96 Hz, 2H), 4.32 (s, 2H), 3.77 (s, 3H), 2.71 (d, J = 7.17 Hz, 2H), 2.23-2.12 (m, 1H), 1.39 (t, J = 7.14 Hz, 3H), 0.96 (d, J = 6.57 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 158.7, 152.9, 144.3, 142.7, 138.6, 130.2, 129.4, 113.8, 63.4, 55.2, 42.1, 32.7, 28.1, 22.4, 14.2; HRMS (EI) calcd for C18H23ClN2O2S 366.1169, found 366.115. 2-(4-Methoxybenzylthio)-6-benzyl-5-chloro-3-methyl-pyrazine (5d): colorless oil; yield 72%; 1H NMR (300 MHz, CDCl3) δ 7.29-7.27 (m, 5H), 7.19 (d, J = 8.49 Hz, 2H), 6.77 (d, J = 8.46 Hz, 2H), 4.29 (s, 2H), 4.24 (s, 2H), 3.77 (s, 3H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.7, 152.6, 149.9, 148.6, 142.0, 137.5, 130.1, 129.2, 128.4, 126.6, 113.8, 55.2, 40.3, 33.5, 20.6; HRMS (EI) calcd for C20H19ClN2OS 370.0907, found 370.0888. General Procedure for the Preparation of 9a-j. A mixture of pyrazine 5 (0.5 mmol), boronic acid 8 (2 equiv), Pd(PPh3)4 (5 mol %), and CuTC (1.5 equiv) in THF (4 mL) was irradiated in a 15 mL sealed tube at a ceiling temperature of 120 °C using a maximum power of 500 W for 30 min. After 30 min, a second lot of the above reactants, boronic acid 8 (1 equiv), Pd(PPh3)4 (5 mol %), and CuTC (1 equiv), was added, and again, the reaction was run for 30 min with the same conditions. After completion of the reaction, the reaction mixture was filtered through Celite and the filtrate was diluted with ethylacetate (200 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over magnesium sulfate and distilled under reduced pressure, and the residue was purified by silica gel column chromatography (from 0 to 30% of ethyl acetate in heptane) to afford compounds 9a-j. 5-Chloro-3-methoxy-2-(4-methoxyphenyl)pyrazines (9a): light yellow solid; mp 69-71 °C; yield 84%; 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 8.09 (d, J = 8.85 Hz, 2H), 6.98 (d, J = 8.85 Hz, 2H), 4.06 (s, 3H), 3.97 (s, 3H); HRMS (EI) calcd for C12H11ClN2O2 250.0509, found 250.0514. 5-Chloro-3-methoxy-2-(3,4-dimethoxyphenyl)pyrazines (9b): white solid; mp 118-120 °C; yield 69%; 1H NMR (300 MHz, CDCl3) δ 8.20 (s, 1H), 7.74 (d, J = 8.46 Hz, 1H), 7.65 (s, 1H), 6.95 (d, J = 8.46 Hz, 1H), 4.07 (s, 3H), 3.96-3.94 (m, 6H); 13 C NMR (75 MHz, CDCl3) δ 156.5, 150.2, 148.7, 142.3, 140.5, 134.5, 127.4, 122.2, 111.8, 110.4, 55.9, 54.5; HRMS (EI) calcd for C13H13ClN2O3 280.0615, found 280.0578. 5-Chloro-2-(3,4-difluorophenyl)-3-methoxypyrazine (9c): white solid; mp 113-115 °C; yield 75%; 1H NMR (300 MHz, CDCl3) J. Org. Chem. Vol. 76, No. 3, 2011

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FIGURE 2. Structure of azides 13a-e. TABLE 6.

Synthesis of Triazoles 14a-ja

entry

substrate

azide R4-N3

product

yield (%)

1 2 3 4 5 6 7 8 9 10b

12a 12b 12b 12b 12c 12c 12d 12d 12d 12d

13a 13b 13c 13d 13a 13b 13a 13b 13e TMS-N3

14a 14b 14c 14d 14e 14f 14g 14h 14i 14j (R4 = H)

82 69 56 38 92 71 73 63 78 80

a

All the reactions were run on a 0.1 mmol scale of 12a-d in a multimode microwave apparatus. bThe protective group (TMS) was cleaved in situ applying the described reaction conditions.

δ 8.23 (s, 1H), 8.01-7.88 (m, 2H), 7.28-7.19 (m, 1H), 4.09 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 152.6, 151.7, 151.6, 149.4, 149.3, 148.5, 148.3, 143.7, 138.3, 134.9, 131.7, 131.6, 129.9, 125.4 (2), 125.3 (2), 118.3, 118.0, 117.1, 116.9, 113.9, 54.7; HRMS (EI) calcd for C11H7ClF2N2O 256.0215, found 256.0227. 5-Chloro-2-(3-(trifluoromethyl)phenyl)-3-methoxypyrazine (9d): white solid; mp 38-40 °C; yield 80%; 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 8.27-8.25 (m, 2H), 7.69 (d, J = 7.53 Hz, 1H), 7.58 (t, J = 7.74 Hz, 1H), 4.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 156.9, 144.1, 139.1, 135.5, 135.1, 132.1, 130.9, 130.5, 128.7, 126.0, 125.9 (2), 125.8, 122.2, 54.7; HRMS (EI) calcd for C12H8ClF3N2O 288.0277, found 288.0276. 2-Chloro-6-methoxy-5-(4-methoxyphenyl)-3-methylpyrazine (9e): white solid; mp 71-73 °C; yield 86%; 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J = 8.85 Hz, 2H), 6.98 (d, J = 8.85 Hz, 2H), 4.03 (s, 3H), 3.86 (s, 3H), 2.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.4, 164.9, 142.1, 140.9, 139.7, 130.4, 127.5, 113.6, 55.3, 54.3, 20.7; HRMS (EI) calcd for C13H13ClN2O2 264.0666, found 264.0663. 2-Chloro-6-methoxy-5-(3,4-dimethoxyphenyl)-3-methylpyrazine (9f): light yellow solid; mp 94-96 °C; yield 93%; 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J = 8.46 Hz, 1H), 7.65 (d, J = 1.14 Hz, 1H), 6.94 (d, J = 8.46 Hz, 1H), 4.03 (s, 3H), 3.96 (s, 3H), 3.93 (s, 3H), 2.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 154.9, 150.0, 148.7, 142.1, 139.4, 129.6, 127.6, 122.2, 113.8, 111.9, 110.5, 55.9 (2), 54.4, 20.7; HRMS (EI) calcd for C14H15ClN2O3 294.0771, found 294.0765. 2-(4-tert-Butylphenyl)-5-chloro-3-methoxy-6-methylpyrazine (9g): colorless liquid; yield 92%; 1H NMR (300 MHz, CDCl3) 854

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δ 7.95 (d, J = 8.46 Hz, 2H), 7.48 (d, J = 8.67 Hz, 2H), 4.02 (s, 3H), 2.60 (s, 3H), 1.34 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 155.1, 152.4, 142.3, 141.4, 140.0, 132.1, 128.6, 125.2, 54.3, 34.7, 31.2, 20.7; HRMS (EI) calcd for C16H19ClN2O 290.1186, found 290.1186. 2-Chloro-6-ethoxy-3-isobutyl-5-(3,4-dimethoxyphenyl)pyrazine (9h): off-white solid; mp 72-74 °C; yield 79%; 1H NMR (300 MHz, CDCl3) δ 7.82-7.79 (m, 2H), 6.95 (d, J = 8.28 Hz, 1H), 4.47 (q, J = 6.99 Hz, 2H), 3.95-3.94 (m, 6H), 2.80 (d, J = 7.17 Hz, 2H), 2.29-2.20 (m, 1H), 1.47 (t, J = 6.99 Hz, 3H), 1.00 (d, J = 6.57 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 154.2, 149.9, 148.4, 144.7, 141.0, 138.9, 128.0, 122.2, 112.0, 110.6, 63.1, 55.9, 55.7, 42.1, 28.1, 22.4, 14.4; HRMS (EI) calcd for C18H23ClN2O3 350.1397, found 350.1387. 2-Chloro-6-ethoxy-5-(3,4-difluorophenyl)-3-isobutylpyrazine (9i): white solid; yield 72%; 1H NMR (300 MHz, CDCl3) δ 8.07-7.94 (m, 2H), 7.20 (t, J = 8.46 Hz, 1H), 4.49 (q, J = 7.14 Hz, 2H), 2.79 (d, J = 7.14 Hz, 2H), 2.30-2.16 (m, 1H), 1.47 (t, J=7.17 Hz, 3H), 0.99 (d, J = 6.60 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 154.3, 152.6, 152.4, 151.7, 151.5, 149.2, 149.1, 148.4, 148.3, 145.2, 142.5, 136.8, 132.3 (2), 132.1, 125.4 (2), 125.3 (2), 118.2, 118.0, 117.0, 116.8, 63.5, 42.1, 29.7, 28.1, 22.4, 14.4; HRMS (EI) calcd for C16H17ClF2N2O 326.0997, found 326.1014. 2-Benzyl-3-chloro-6-(3,4-dimethoxyphenyl)-5-methylpyrazine (9j): colorless oil; yield 80%; 1H NMR (300 MHz, CDCl3) δ 7.37-7.21 (m, 6H), 7.18-7.14 (m, 2H), 6.96 (d, J = 7.92 Hz, 1H), 4.32 (s, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 2.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 151.0, 150.4, 149.7, 149.0, 148.8,

Modha et al. 144.9, 137.5, 130.0, 129.1, 128.4, 126.6, 121.8, 112.4, 110.7, 55.9 (2), 40.6, 22.6; HRMS (EI) calcd for C20H19ClN2O2 354.1135, found 354.1145. General Procedure for the Preparation of 10a-e. The general procedures for the synthesis of compounds 10a-d27 and 10e28 are the same as described in the literature starting from their respective thiols. Data for compounds 10a,29 10b,30 and 10e28 were in accordance with the already published ones in the literature. 2-(4-Methoxybenzylthio)-4,6-dimethylpyrimidine (10c): white solid; yield 79%; 1H NMR (300 MHz, CDCl3) δ 7.36 (d, J = 8.64 Hz, 2H), 6.82 (d, J = 8.67 Hz, 2H), 6.68 (s, 1H), 4.36 (s, 2H), 3.78 (s, 3H), 2.40 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 166.9, 158.6, 130.2, 130.1, 115.6, 113.7, 55.2, 34.6, 23.8; HRMS (EI) calcd for C14H16N2OS 260.0983, found 260.0998. 2-(4-Methoxybenzylthio)-1-methyl-1H-imidazole (10d): white solid; yield 54%; 1H NMR (300 MHz, CDCl3) δ 7.11 (s, 1H), 7.05 (d, J = 8.46 Hz, 2H), 6.86 (s, 1H), 6.78 (d, J = 8.64 Hz, 2H), 4.12 (s, 2H), 3.77 (s, 3H), 3.28 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.9, 140.7, 129.9, 129.8, 129.7, 122.3, 113.8, 55.2, 39.5, 33.1; HRMS (EI) calcd for C12H14N2OS 234.0827, found 234.0840. General Procedure for the Preparation of 11a-i. The general procedure for the preparation of 11a-i is the same as that for 9a-j. Data for compounds 11a,31 11b,32 11c,33 11d,34 11e,35 11f,36 11g,37 and 11h38 were in accordance with the published data. 5-(3,4-Dimethoxyphenyl)-1-phenyl-1H-tetrazole (11i): white solid; yield 75%; 1H NMR (400 MHz, CDCl3) δ 7.56 (m, 3H), 7.43 (dd, J = 1.52, 7.68 Hz, 2H), 7.15 (d, 2.04 Hz, 1H), 7.07 (dd, J = 2.0, 8.3 Hz, 1H), 6.83 (d, J = 8.32 Hz, 1H), 3.89 (s, 3H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 151.4, 149.1, 134.9, 130.4, 129.8, 125.6, 122.1, 115.7, 111.6, 111.1, 55.9, 55.8; HRMS (EI) calcd for C15H14N4O2 282.1117, found 282.1131. General Procedure for the Preparation of 12a-d. A mixture of pyrazine 9 (2.0 mmol), triisopropylsilylacetylene (1.5 equiv), Pd(PPh3)2Cl2 (5 mol %), CuI (10 mol %), and tetrabutylammonium iodide (TBAI, 1.2 equiv) in DMF/TEA (1:1, 4 mL) was irradiated in a 15 mL sealed tube at a ceiling temperature of 80 °C using a maximum power of 80 W for 20 min. After completion of the reaction, the reaction mixture was diluted with dichloromethane (200 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over magnesium sulfate, distilled under reduced pressure. The obtained residue was dissolved in DCM/THF (1.5:1, 5 mL), and TBAF solution in THF (1M, 2 equiv) was added dropwise. The reaction mixture was stirred at room temperature for 3-5 min. After completion of the reaction, solvents were removed under reduced pressure and the residue was directly subjected to flash column chromatography on short silica gel pads (from 0 to 30% ethyl acetate in (27) Radi, M.; et al. ChemMedChem 2008, 3, 573. (28) Pellecchia, M. Patent PCT WO 2008/118626 A2, 2008. (29) Ko, H. M.; Lee, D. G.; Kim, M. A.; Kim, H. J.; Park, J.; Lah, M. S.; Lee, E. Tetrahedron 2007, 63, 5797. (30) Pathak, A. K.; Pathak, V.; Seitz, L. E.; Suling, W. J.; Reynolds, R. C. J. Med. Chem. 2004, 47, 273. (31) Boeini, H. Z.; Najafabadi, K. H. Eur. J. Org. Chem. 2009, 4926. (32) Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.; Gao, G.; You, J. Angew. Chem., Int. Ed. 2009, 48, 3296. (33) Jaseer, E. A.; Prasad, D. J. C.; Dandapat, A.; Sekar, G. Tetrahedron Lett. 2010, 51, 5009. (34) Begouin, J.-M.; Gosmini, C. J. Org. Chem. 2009, 74, 3221. (35) Mehta, V. P.; Modha, S. G.; Van der Eycken, E. J. Org. Chem. 2009, 74, 6870. (36) Ghosh, U.; Katzenellenbogen, J. A. J. Heterocycl. Chem. 2002, 39, 1101. (37) Schmitt, J.-L.; Stadler, A.-M.; Kyritsakas, N.; Lehn, J.-M. Helv. Chim. Acta 2003, 86, 1598. (38) Spulak, M.; Lubojacky, R.; Senel, P.; Kunes, J.; Pour, M. J. Org. Chem. 2010, 75, 241.

JOC Article heptane) to afford the desired terminal acetylenes 12a-d in good yields. 5-Ethynyl-3-methoxy-2-(4-methoxyphenyl)pyrazine (12a): light yellow solid; yield 78%; 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 8.10 (d, J = 8.85 Hz, 2H), 6.99 (d, J = 8.88 Hz, 2H), 4.06 (s, 3H), 3.87 (s, 3H), 3.29 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 160.8, 156.7, 142.7, 139.6, 131.7, 130.8, 127.7, 113.6, 80.5, 79.8, 55.3, 54.0; HRMS (EI) calcd for C14H12N2O2 240.0899, found 240.0897. 2-Ethynyl-6-methoxy-5-(4-methoxyphenyl)-3-methylpyrazine (12b): dark brown solid; mp 128-130 °C; yield 91%; 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J = 8.85 Hz, 2H), 6.98 (d, J = 8.85 Hz, 2H), 4.03 (s, 3H), 3.86 (s, 3H), 3.45 (s, 1H), 2.65 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.7, 155.1, 147.7, 141.5, 130.8, 130.0, 127.9, 113.6, 82.1, 80.9, 55.3, 53.9, 20.9; HRMS (EI) calcd for C15H14N2O2 254.1055, found 254.1065. 2-Ethynyl-6-methoxy-5-(3,4-dimethoxyphenyl)-3-methylpyrazine (12c): light brown solid; mp 145-147 °C; yield 80%; 1H NMR (300 MHz, CDCl3) δ 7.79 (dd, J = 1.71, 8.47 Hz, 1H), 7.71 (d, J = 1.50 Hz, 1H), 6.94 (d, J = 8.46 Hz, 1H), 4.04 (s, 3H), 3.96 (s, 3H), 3.94 (s, 3H), 3.46 (s, 1H), 2.66 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 155.2, 150.3, 148.6, 147.7, 141.2, 130.1, 128.0, 122.6, 112.1, 110.5, 82.2, 80.8, 55.9, 53.9, 20.9; HRMS (EI) calcd for C16H16N2O3 284.1161, found 284.1170. 2-Ethoxy-6-ethynyl-5-isobutyl-3-(3,4-dimethoxyphenyl)pyrazine (12d): pink solid; mp 108-110 °C; yield 59%; 1H NMR (300 MHz, CDCl3) δ 7.88-7.86 (m, 2H), 6.95 (d, J = 8.28 Hz, 1H), 4.48 (q, J = 6.96 Hz, 2H), 3.95-3.94 (m, 6H), 3.39 (s, 1H), 2.86 (d, J = 7.14 Hz, 2H), 2.31-2.18 (m, 1H), 1.47 (t, J = 7.14 Hz, 3H), 0.99 (d, J = 6.78 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 154.7, 150.5, 150.2, 148.4, 140.7, 130.2, 128.4, 122.7, 112.3, 110.5, 81.5, 81.0, 62.5, 55.9, 55.7, 42.7, 28.8, 22.4, 14.5; HRMS (EI) calcd for C20H24N2O3 340.1787, found 340.1775. General Procedure for the Preparation of 13a-e. All protected sugar azides23 13a-d and the benzyl azide24 13e were synthesized according to literature procedures. General Procedure for the Preparation of 14a-j. A mixture of pyrazine 12 (0.1 mmol), azide 13 (1.2 equiv), copper turnings (2 equiv), CuSO4 solution in water (1M, 5 mol %), and tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine ligand (TBTA, 5 mol %) in THF/i-PrOH/H2O (3:1:1, 5 mL) was irradiated in a 15 mL sealed tube at a ceiling temperature of 90 °C using a maximum power of 200 W for 20 min. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over magnesium sulfate, distilled under reduced pressure. The obtained residue was subjected to silica gel column chromatography (from 0 to 50% ethyl acetate in heptane) to afford the desired compounds 14a-j. (2R,3R,4R,5R)-2-(Benzoyloxymethyl)-5-(4-(6-methoxy-5-(4methoxyphenyl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)tetrahydrofuran-3,4-diyl Dibenzoate (14a): white solid; mp 77-79 °C; yield 82%; 1H NMR (300 MHz, CDCl3) δ 8.96 (s, 1H), 8.30 (s, 1H), 8.11 (d, J = 8.49 Hz, 2H), 8.03-7.96 (m, 6H), 7.62-7.34 (m, 9H), 7.00 (d, J = 8.46 Hz, 2H), 6.54 (d, J = 3.03 Hz, 1H), 6.37 (bs, 1H), 6.18 (t, J = 5.25 Hz, 1H), 4.94-4.88 (m, 2H), 4.63 (dd, J = 3.39, 11.97 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.1, 165.1 (2), 160.5, 156.8, 146.7, 141.9, 138.9, 133.9, 133.7, 133.3, 132.8, 130.6, 129.9, 129.8, 129.6, 129.1, 128.6, 128.5, 128.4, 128.2, 121.5, 113.6, 90.5, 81.4, 75.3, 71.5, 63.5, 55.3, 53.4; MS (ESIþ) calcd for C40H33N5O9 727.7, found 750.3 [M þ Na]þ, 1478.2 [2M þ Na]þ. ((2R,3S,5R)-3-(4-Chlorobenzoyloxy)-5-(4-(6-methoxy-5-(4methoxyphenyl)-3-methyl-pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)tetrahydro-furan-2-yl)methyl-4-chlorobenzoate (14b): yellow solid; mp 66-67 °C; yield 69%; 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 8.14 (d, J = 8.67 Hz, 2H), 8.01 (d, J = 8.46 Hz, 2H), 7.85 (d, J = 8.46 Hz, 2H), 7.47 (d, J = 8.31 Hz, 2H), 7.31 (d, J = 8.49 Hz, J. Org. Chem. Vol. 76, No. 3, 2011

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JOC Article 2H), 7.00 (d, J = 8.64 Hz, 2H), 6.52 (t, J = 5.85 Hz, 1H), 5.87 (bs, 1H), 4.75-4.69 (m, 2H), 4.54-4.51 (m, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.51-3.42 (m, 1H), 2.98-2.89 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 165.2, 64.9, 160.4, 154.7, 148.3, 142.2, 140.2, 139.8, 136.2, 131.1, 130.9, 130.6, 128.9, 128.2, 127.6, 127.4, 123.2, 113.6, 88.7, 83.5, 74.8, 63.9, 55.3, 53.3, 37.8, 22.4; MS (ESIþ) calcd for C34H29Cl2N5O7 690.5, found 691.2 [M]þ, 1403.4 [2M þ Na]þ. (2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-(4-(6-methoxy-5-(4methoxyphenyl)-3-methyl-pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl Triacetate (14c): white solid; mp 182-185 °C; yield 56%; 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 8.14 (d, J = 8.85 Hz, 2H), 7.00 (d, J = 8.85 Hz, 2H), 5.98 (d, J = 9.42 Hz, 1H), 5.58 (t, J = 9.42 Hz, 1H), 5.46 (t, J = 9.42 Hz, 1H), 5.30 (t, J = 9.78 Hz, 1H), 4.37-4.31 (m, 1H), 4.18 (d, J = 12.63 Hz, 1H), 4.08-4.04 (m, 4H), 3.87 (s, 3H), 2.96 (s, 3H), 2.09 (s, 6H), 2.04 (s, 3H), 1.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.5, 169.9, 169.4, 169.0, 160.4, 154.9, 148.5, 142.3, 140.5, 136.0, 130.6, 128.2, 122.3, 113.6, 85.8, 75.2, 70.3, 67.7, 61.6, 55.3, 53.5, 22.4, 20.7, 20.5 (2), 20.2; MS (ESIþ) calcd for C29H33N5O11 627.5, found 628.8 [M]þ, 1277.8 [2M þ Na]þ. (2R,3S,4S,5R,6R)-2-(Acetoxymethyl)-6-(4-(6-methoxy-5-(4methoxyphenyl)-3-methyl-pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl Triacetate (14d): white solid; mp 81-83 °C; yield 38%; 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 8.14 (d, J = 8.85 Hz, 2H), 7.00 (d, J = 8.85 Hz, 2H), 5.93 (d, J = 9.21 Hz, 1H), 5.69 (t, J = 9.78 Hz, 1H), 5.59 (bs, 1H), 5.30 (dd, J = 3.39, 10.33 Hz, 1H), 4.28-4.20 (m, 3H), 4.10 (s, 3H), 3.87 (s, 3H), 2.96 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 1.93 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.3, 170.0, 169.8, 169.2, 160.4, 154.9, 148.4, 142.4, 140.4, 136.2, 130.6, 128.2, 122.3, 113.6, 86.3, 74.2, 70.8, 67.8, 66.8, 61.2, 55.3, 53.6, 22.4, 20.7, 20.6, 20.5, 20.3; MS (ESIþ) calcd for C29H33N5O11 627.5, found 628.9 [M]þ, 1277.6 [2M þ Na]þ. (2R,3R,4R,5R)-2-(Benzoyloxymethyl)-5-(4-(5-(3,4-dimethoxyphenyl)-6-methoxy-3-methyl-pyrazin-2-yl)-1H-1,2,3-triazol1-yl)tetrahydro-furan-3,4-diyl Dibenzoate (14e): white solid; mp 83-85 °C; yield 92%; 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 8.03-7.96 (m, 6H), 7.82 (d, J = 8.46 Hz, 1H), 7.77 (s, 1H), 7.62-7.55 (m, 2H), 7.50-7.35 (m, 7H), 6.96 (d, J = 8.46 Hz, 1H), 6.54 (d, J = 1.14 Hz, 1H), 6.38 (t, J = 4.14 Hz, 1H), 6.22 (t, J = 5.28 Hz, 1H), 4.96-4.87 (m, 2H), 4.63 (dd, J = 3.96, 12.24 Hz, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 3.90 (s, 3H), 2.97 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.1, 165.1, 154.7, 150.0, 148.7, 148.3, 142.2, 139.9, 136.2, 13.9, 133.7, 133.3, 129.9, 129.8, 129.6, 129.1, 128.6 (2), 128.5, 128.4 (2), 123.3, 122.4, 112.0, 110.5, 90.4, 81.3, 75.4, 71.5, 63.5, 55.9, 53.4, 35.4, 31.8, 26.4, 22.6, 22.5, 14.1; MS (ESIþ) calcd for C42H37N5O10 771.7, found 772.4 [M]þ, 1565.0 [2M þ Na]þ. ((2R,3S,5R)-3-(4-Chlorobenzoyloxy)-5-(4-(5-(3,4-dimethoxyphenyl)-6-methoxy-3-methyl-pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)tetra-hydrofuran-2-yl)methyl 4-chlorobenzoate (14f): yellow solid; mp 99-101 °C; yield 71%; 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 8.01 (d, J = 8.46 Hz, 2H), 7.86-7.81 (m, 3H), 7.78 (s, 1H), 7.47 (d, J = 8.31 Hz, 2H), 7.31 (d, J = 8.46 Hz, 2H), 6.96 (d, J = 8.46 Hz, 1H), 6.52 (t, J = 5.82 Hz, 1H), 5.87 (bs, 1H), 4.76-4.69 (m, 2H), 4.53 (d, J = 7.53 Hz, 1H), 3.99-3.95 (m, 9H), 3.51-3.43 (m, 1H), 3.02-2.89 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 165.1, 164.9, 154.7, 150.0, 148.7, 148.2, 142.2, 140.3, 139.9, 139.8, 136.3, 131.1, 130.9, 128.9, 128.7, 128.4, 127.6, 127.4, 123.2, 122.4, 112.0, 110.5, 88.7, 83.5, 74.8, 63.9, 55.9, 53.4, 37.8, 35.4, 31.8, 26.4, 26.3, 22.6, 22.4, 14.1; MS (ESIþ) calcd for C35H31Cl2N5O8 720.5, found 721.7 [M]þ, 1463.2 [2M þ Na]þ. (2R,3R,4R,5R)-2-(Benzoyloxymethyl)-5-(4-(5-(3,4-dimethoxyphenyl)-6-ethoxy-3-isobutyl-pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)tetrahydro-furan-3,4-diyl Dibenzoate (14g): light yellow solid; mp 70-72 °C; yield 73%; 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 8.03-7.92 (m, 8H), 7.59-7.54 (m, 2H), 7.47-7.32 (m, 7H), 6.97 856

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Modha et al. (d, J = 8.46 Hz, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 6.22 (t, J = 4.89 Hz, 1H), 4.96-4.84 (m, 2H), 4.67-4.63 (m, 1H), 4.35 (t, J = 6.57 Hz, 2H), 3.98-3.95 (m, 6H), 3.41-3.21 (m, 2H), 2.33-2.29 (m, 1H), 1.44 (t, J = 6.03 Hz, 3H), 1.01 (d, J = 6.03 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 166.1, 165.1, 154.1, 149.8, 148.4 (2), 145.3, 139.3, 136.2, 133.9, 133.7, 133.3, 129.9, 129.7, 129.1, 128.8, 128.6, 128.5, 128.4, 123.6, 122.4, 112.2, 110.6, 90.4, 81.1, 75.4, 71.5, 63.6, 62.0, 55.9, 55.7, 42.4, 35.4, 30.9, 28.5, 26.4, 22.6, 22.5 (2), 14.5; MS (ESIþ) calcd for C46H45N5O10 827.8, found 828.3 [M]þ, 1677.1 [2M þ Na]þ. ((2R,3S,5R)-3-(4-Chlorobenzoyloxy)-5-(4-(5-(3,4-dimethoxyphenyl)-6-ethoxy-3-isobutyl-pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)tetrahydro-furan-2-yl)methyl 4-chlorobenzoate (14h): light yellow solid; mp 59-61 °C; yield 63%; 1H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H), 8.00 (d, J = 7.74 Hz, 2H), 7.92-7.86 (m, 4H), 7.45 (d, J = 7.92 Hz, 2H), 7.32 (d, J = 7.92 Hz, 2H), 6.98 (d, J = 8.67 Hz, 1H), 6.51 (t, J=5.64 Hz, 1H), 5.87 (bs, 1H), 4.70-4.67 (m, 2H), 4.57-4.51 (m, 1H), 4.41 (q, 6.39 Hz, 2H), 3.98 (s, 3H), 3.95 (s, 3H), 3.54-3.45 (m, 1H), 3.39-3.21 (m, 2H), 2.95-2.90 (m, 1H), 2.34-2.25 (m, 1H), 1.47 (t, J = 6.96 Hz, 3H), 1.01 (d, J = 6.57 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 165.2, 164.9, 154.2, 149.8, 148.4 (2), 145.2, 140.2, 139.8, 138.3, 136.3, 131.1, 128.9, 128.8, 127.7, 127.5, 123.5, 122.4, 112.2, 110.6, 88.7, 83.5, 74.9, 64.0, 62.0, 55.9, 55.7, 42.4, 37.6, 35.4, 31.8, 30.9, 28.5, 26.4, 22.6, 22.5 (2), 14.6, 14.1; MS (ESIþ) calcd for C39H39Cl2N5O8 776.6, found 777.2 [M]þ, 1575.6 [2M þ Na]þ. 2-(1-Benzyl-1H-1,2,3-triazol-4-yl)-6-ethoxy-3-isobutyl-5-(3,4dimethoxyphenyl)pyrazine (14i): yellow solid; mp 137-139 °C; yield 78%; 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.91-7.89 (m, 2H), 7.41-7.33 (m, 5H), 6.96 (d, J = 9.03 Hz, 1H), 5.61 (s, 2H), 4.44 (q, J = 7.23 Hz, 2H), 3.96 (s, 3H), 3.94 (s, 3H), 3.32 (d, J = 6.96 Hz, 2H), 2.33-2.22 (m, 1H), 1.46 (t, J = 6.99 Hz, 3H), 0.99 (d, J = 6.60 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 154.2, 149.8, 148.4, 148.3, 145.3, 139.0, 136.8, 134.7, 129.1, 128.8, 128.7, 128.0, 124.0, 122.3, 112.2, 110.6, 62.0, 55.9, 55.7, 54.1, 42.5, 28.5, 22.5, 14.5; HRMS (EI) calcd for C27H31N5O3 473.2427, found 473.2420. 2-Ethoxy-5-isobutyl-3-(3,4-dimethoxyphenyl)-6-(1H-1,2,3triazol-4-yl)pyrazine (14j): green solid; mp 202-204 °C; yield 80%; 1H NMR (400 MHz, DMSO) δ 15.3 (bs, 1H), 8.38 (bs, 1H), 7.86 (d, J = 1.50 Hz, 1H), 7.82 (dd, J = 1.50, 6.33 Hz, 1H), 7.09 (d, J = 6.42 Hz, 1H), 4.52 (q, J = 5.28 Hz, 2H), 3.83-3.82 (m, 6H), 2.50 (merged in solvent peak, 2H), 2.21-2.13 (m, 1H), 1.44 (t, J = 5.28 Hz, 3H), 0.93 (d, J = 4.92 Hz, 6H); 13C NMR (75 MHz, DMSO) δ 153.8, 149.7, 148.0, 127.8, 121.9, 112.1, 111.2, 61.9, 55.4, 55.2, 54.8, 41.9, 27.8, 22.2, 14.3; HRMS (EI) calcd for C20H25N5O3 383.1957, found 383.1973.

Acknowledgment. The authors thank the FWO (Fund for Scientific Research-Flanders (Belgium)) and the Research Fund of the Katholieke Universiteit Leuven for financial support to the laboratory. J.C.T. is grateful to EMECW15 (Erasmus Mundus External Cooperation Window Lot 15 India) for obtaining a postdoctoral scholarship. V.P.M. is grateful to the IRO (Interfacultaire Raad voor Ontwikkelingssamenwerking) for obtaining a doctoral scholarship. D.E. is grateful to the Katholieke Universiteit Leuven for obtaining a postdoctoral scholarship. The authors thank Ir. B. Demarsin for HRMS measurements. This paper is dedicated to Prof. Ferenc F€ ul€ op on the occasion of his 60th birthday. Supporting Information Available: General experimental procedures, spectroscopic and analytical data, and copies of 1H and 13C NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.